Department of Pathology, Hebei Medical University, Shijiazhuang, China.
Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, China.
Cell Death Dis. 2022 Jul 30;13(7):663. doi: 10.1038/s41419-022-05120-0.
Sestrin2 is identified as a stress-induced protein and could functionate in many aspects. In our study, we investigated the latent impact of Sestrin2 on podocyte injury and its molecular mechanism in vivo and in vitro in diabetic kidney disease (DKD). Sestrin2 was low-expressed in renal biopsies from individuals with DKD, the glomeruli from diabetic mice, and mouse podocytes exposed to high glucose (HG). Sestrin2 overexpression ameliorated HG-induced phenotypic alterations, apoptosis, and oxidative stress in conditionally immortalized mouse podocytes and modulated the activity of Thrombospondin-1 (TSP-1)/transforming growth factor (TGF-β1)/Smad3 pathway in podocytes. Moreover, TSP-1 inhibitor LSKL or TGF-β blocker Pirfenidone arrested podocyte injury induced by HG. Streptozotocin (STZ) was employed to render equivalent diabetes in B6-TgN (CMV-Sestrin2) (TgN) and wild-type (WT) control mice. Sestrin2 alleviated increased levels of 24-h urinary protein, blood urea nitrogen, serum creatinine and triglyceride, and urine 8-OHdG in diabetic mice. Podocyte phenotypic alterations, increased expression of apoptosis-associated proteins and podocyte loss were observed in WT but not in diabetic TgN mice, as well as oxidative stress. Additionally, TSP-1/TGF-β1/Smad3 signaling pathway was also suppressed in glomeruli of diabetic TgN mice. Thus, Sestrin2 mitigates podocyte injury in DKD via orchestrating TSP-1/TGF-β1/Smad3 pathway, underlining Sestrin2 as a promising therapeutic target for DKD.
Sestrin2 被鉴定为一种应激诱导蛋白，可在许多方面发挥作用。在我们的研究中，我们在体内和体外研究了 Sestrin2 对足细胞损伤的潜在影响及其在糖尿病肾病 (DKD) 中的分子机制。在 DKD 患者的肾活检组织、糖尿病小鼠的肾小球和高糖 (HG) 暴露的小鼠足细胞中，Sestrin2 的表达水平较低。过表达 Sestrin2 可改善条件永生化小鼠足细胞中 HG 诱导的表型改变、凋亡和氧化应激，并调节足细胞中血小板反应蛋白 1 (TSP-1)/转化生长因子 (TGF-β1)/Smad3 通路的活性。此外，TSP-1 抑制剂 LSKL 或 TGF-β 阻滞剂 Pirfenidone 可阻止 HG 诱导的足细胞损伤。链脲佐菌素 (STZ) 用于使 B6-TgN (CMV-Sestrin2) (TgN) 和野生型 (WT) 对照小鼠产生等效的糖尿病。Sestrin2 可减轻糖尿病小鼠 24 小时尿蛋白、血尿素氮、血清肌酐和甘油三酯以及尿 8-OHdG 的升高。在 WT 小鼠中观察到足细胞表型改变、凋亡相关蛋白表达增加和足细胞丢失，但在糖尿病 TgN 小鼠中没有观察到，同时还观察到氧化应激。此外，TSP-1/TGF-β1/Smad3 信号通路在糖尿病 TgN 小鼠的肾小球中也受到抑制。因此，Sestrin2 通过协调 TSP-1/TGF-β1/Smad3 通路减轻 DKD 中的足细胞损伤，强调 Sestrin2 是 DKD 有前途的治疗靶点。
